JPH0647579B2 - Novel pyrimidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hydroxy and alkoxy substituted pyrimidines, more particularly 2-amino and 2-substituted amino-4.
-Substituted-5- (hydroxy or alkoxy) pyrimidines, optionally substituted at the 6-position.

(Prior Art) Bray et al., Biochemistry Journal
chem.J.) 1951, 48, 400 is 2-amino-4,6
-Dimethyl-5-hydroxypyrimidine and a method for producing the same are disclosed, but nothing about their pharmaceutical use is shown.

British patent application 2045756 discloses 2-isopropylamino-5-hydroxypyrimidine for the treatment of muscular dystrophi. This prior published application does not show any substitution at the 4 and 6 positions of the pyrimidine group of the above compound.

Chemical Abstract 94; 121446s (198
1) is 2-dimethylamino-4,6-diphenyl-5-
It discloses a hydroxypyrimidine but does not disclose any of the pharmaceutical or other properties of this compound.

U.S. Pat. No. 4,554,276 discloses 2-amino-4-methyl-5-hydroxypyrimidines for pharmaceutical use similar to the compounds of the present invention.

Currently, the treatment of asthma is centered on the use of bronchodilators to reduce acute bronchospasm.
Acute bronchospasm is a clear manifestation of chronic inflammation.
Leukotrienes may show efficacy in both bronchospasm and chronic inflammation. Leukotrienes are known to be effective vasodilators and chemical agents. Leukotrienes are also produced in allergic reactions, resulting in a slow contraction of lung tissue in vitro. This is the reason why inhibitors of leukotriene synthesis are used to treat asthma and other lung disorders.

Chronic gastric and duodenal ulcers (collectively known as peptic ulcers) are given various treatments, including special diets, medications, and surgery, depending on the severity of the symptoms. Therapeutic agents of particular value useful for the treatment of hyperacidity and peptic ulcers, shall apply histamine -H ₂ receptor antagonist, which is of H ₂ animal body - is a physiologically active compound receptor site histamine Block the action of, thereby inhibiting the secretion of gastric acid.

(Means for Solving the Problem) According to the present invention, a substituted pyrimidine of the following formula is provided: [Wherein R ₁ is hydrogen or (C ₁ -C ₁₅ ) alkyl; R ₂
Is hydrogen, (C ₁ -C ₁₅ alkyl, cyclopentyl, cyclohexyl, (C ₃ -C ₁₅ ) alkenyl, phenyl, or (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety is fluoro, chloro, (C ₁ -C ₃₎ alkyl, (C
₁ -C ₃₎ one of the alkoxy or CF ₃ or 2
Optionally substituted with one); or R ₁ and R ₂
Is always connected to the nitrogen atom they are attached to,
One (C ₁ -C ₆₎ alkyl, phenyl or (C ₇ -
C ₂₀ ) forms pyrrolidinyl or piperidyl optionally substituted with phenylalkyl; R ₃ is (C ₁ -C ₆ ).
Alkyl, phenyl, (C ₇ -C ₂₀₎ phenylalanine alkyl (wherein phenyl moiety fluorine, chlorine, (C ₁ -
C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ may be substituted with one or two) or one (C ₁ -C ₃ ) alkyl. Good, furyl or thienyl; R ₄ is hydrogen, (C _1-
C ₆₎ alkyl, phenyl or (C ₇ -C ₂₀₎ phenylalanine alkyl (wherein these phenyl are fluorine, chlorine,
(C ₁ -C ₃₎ alkyl, (C ₁ -C ₃₎ alkoxy, or may be by connexion substituted one or two of the CF _3); R ₅ is hydrogen, (C ₁ - C ₆₎ alkyl,
Phenyl or (C ₇ -C ₂₀ ) phenylalkyl (wherein these phenyls are one or two of fluoro, chloro, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ May be substituted with R), but R
_{When 5} is hydrogen and (1) R ₃ and R ₄ are each methyl, R ₁ and R ₂ are not each hydrogen, and (2) when R ₃ and R ₄ are each phenyl, R ₁ And R ₂ are not methyl,
(3) R ₄ is not hydrogen when R ₃ is (C ₁ -C ₆ ) alkyl, and (3) when R ₄ and R ₅ are hydrogen, R ₃ is (C ₁
-C ₆₎ not alkyl. A particular compound of the invention is a compound of formula I wherein R ₁
And R ₅ are as defined above, R ₂ is hydrogen, and (C _1-
C ₁₅₎ alkyl, phenyl, thienyl, furyl, or (C ₇ -C ₂₀₎ phenylalanine alkyl (phenyl moiety wherein the chlorine or (C ₁ -C ₃₎ optionally substituted with one or more of the alkyl R ₃ is (C ₁ −
C ₆ ) alkyl, phenyl (optionally substituted with one or more of fluoro, chloro, methyl, ethyl, methoxy, ethoxy or CF ₃ ), R ₄ is hydrogen,
(C ₁ -C ₆ ) alkyl, phenyl or substituted phenyl, wherein the substituents are one or two methyl or ethyl, and pharmaceutically acceptable acid addition salts thereof.

In general, R ₂ is preferably (C ₈ -C ₉ ) alkyl,
(C ₉ -C ₁₂₎ phenylalanine alkyl, (C ₉ -C ₁₂₎ p- click Rolf enyl alkyl or (C ₁₀ -C ₁₃₎ be a p- methyl-phenylalanine alkyl; R ₃ and R ₄ are preferably each Is methyl; R ₅ is preferably (C ₁ -C ₆ ) alkyl.

Specific compounds of the present invention are: 2- (p-chlorophenylpropylamino) -4,6-dimethyl-5-hydroxypyrimidine, 2- (p-methylphenylpropylamino)-
4,6-dimethyl-5-hydroxypyrimidine, 2-
(N-Nonylamino) -4,6-dimethyl-5-hydroxypyrimidine, 2-phenylhexylamino-4,6
-Dimethyl-5-hydroxypyrimidine, 2-dimethylamino-4-p-fluorphenyl-5-hydroxypyrimidine, 2-phenylhexylamino-4-methyl-
5-methoxypyrimidine, 2-dimethylamino-4-
(3,4-dichlorophenyl) -5-methoxypyridine, 2-dimethylamino-4- (3,4-dichlorophenyl) -5-ethoxypyrimidine, 2- (p-chlorophenylpropyl) -4,6-dimethyl- 5-methoxypyrimidine, 2-phenylhexylamino-4,6-dimethyl-5-methoxypyrimidine, 2-phenylhexylamino-4,6-dimethyl-5-methoxypyrimidine and 2-phenylpentylamino-4, 6-dimethyl-
5-methoxypyrimidine.

Pharmaceutical compositions can be prepared which consist of a compound of formula I'of the compounds of the invention and a pharmaceutical carrier or diluent: [In the formula, R ′ ₁ is hydrogen or (C ₁ -C ₁₅ ) alkyl;
R _'2 is hydrogen, (C ₁ -C ₁₅₎ alkyl, cyclopentyl, cyclohexyl, (C ₃ -C ₁₅₎ alkenyl, phenyl, or (C ₇ -C ₂₀₎ phenylalanine alkyl (wherein phenyl moiety fluorine, chlorine , (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ optionally substituted by one or two); or R ′ ₁ and R ′ ₂ are At any time, with the nitrogen atom to which they are attached, a pyridinyl or piperidyl optionally substituted with one (C ₁ -C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ) phenylalkyl. formed; R _'3
Is (C ₁ -C ₆ ) alkyl, phenyl, (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety is fluoro, chloro, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or It may be substituted with 1 or 2 of CF ₃ ),
Or furyl or thienyl, optionally substituted with one (C ₁ -C ₃ ) alkyl; R ′ ₄ is hydrogen,
(C ₁ -C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ).
Phenylalkyl (wherein these phenyls are fluoro,
Chloro, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ optionally substituted by one or two); R ′ ₅ is hydrogen, ( C ₁ -C ₆₎
Alkyl, or (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety is fluoro, chloro, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ ; May be replaced with one),
When R _'4 and R' ₅ are each hydrogen, R _'3 is (C ₁ -
C ₆₎ not alkyl. ] Preferred compositions corresponding R ', R' _3, R _'4 and R'
Includes compounds having the above generally preferred groups of R ₂ , R ₃ , R ₄ and R ₅ for each of the ₅ groups.

_{R 1, R 2, R 3} , R 4, R 5, R '1, R' 2, R '3, R'
“Alkyl” in the definition of ₄ and R ′ ₅ means a saturated monovalent straight chain or branched chain aliphatic hydrocarbon such as methyl,
It refers to ethyl, propyl, butyl, t-butyl, hexyl, octyl, 2-ethylhexyl and the like.

_{R 2, R 3, R 4} , R 5, R '2, R' 3, R '4 and R' ₅
In the definition of, "phenylalkyl" means a phenyl group added to a saturated divalent straight chain or branched chain aliphatic hydrocarbon, for example, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl,
Hexylphenyl, octylphenyl, 1,1-dimethyl-7-phenylheptyl and the like.

The following reaction steps illustrate a method of making compounds of formula I of the present invention. The compounds of formula I ′ are different from the compounds of formula I, which proviso is that of US Pat. No. 4,554,276.
The compound of No. is excluded. The proviso to Formula I excludes the compounds of Bray et al., Supra, as well as the compounds of Chemical Abstracts, as well as the compounds of US Patent Application No. 538,235. The statements below for the preparation of the compounds of the formula I apply analogously to the compounds of the formula I ′.

Compounds of formula I are those wherein R ₃ and R ₄ are as described above and the acyl is a diketoacyloxy compound of formula II where R ₁ and R ₂ may be any acyl group such as acetyl or benzoyl.
Can be prepared by condensation with a 1,1- (R ₁ , R ₂ ) guanidine salt of formula II in which each is hydrogen or (C ₁ -C ₆ ) alkyl. This condensation is carried out in the presence of an alkaline reagent such as sodium acetate, sodium hydroxide or sodium ethoxide and a polar neutral solvent such as dimethylformamide, dimethylsulfoxide or aqueous alcohol at 80 to 140 ° C., usually 100 ° C. It is carried out for 2 to 24 hours, usually 3 to 5 hours.

The formed compound of formula IV is treated with a hydride reducing agent to form the corresponding 5-hydroxypyrimidines of formula I. Specific hydride reducing agents are, for example, diisobutylaluminum hydride (Dibal) and bis (2-methoxyethoxy) -aluminum sodium hydride. This reaction is generally carried out in a dry inert solvent such as tetrahydrofuran, ether, toluene or benzene at -78 to -10 ° C, usually about -23 ° C.

Alternatively, compound (IV) can be hydrolyzed by conventional techniques, such as reaction with aqueous or alcoholic alkalis, eg under ambient conditions.

Compounds of formula I in which R ₁ is hydrogen and R ₂ is (C ₇ -C ₂₀ ) phenylalkyl can be prepared by reacting compound (II) above with guanidine to form R ₃ and R ₄ as defined above. It can be prepared by forming a compound of V. Reaction conditions are compounds
The condensation of (II) and compound (III) is as described above.

Reaction process The compound (V) formed is then of the formula (In the formula, X is halogen, preferably chlorine; R ₆ is (C ₆
--C ₁₉ ) phenylalkyl (wherein the phenyl moiety may be substituted with 1 to 3 of fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or CF ₃ . A) is a phenylalkanoic acid halide. This reaction to form compound (VI) is
Generally, it is carried out at -20 ° C to room temperature, usually at about 0 ° C for at least 15 minutes, for example 1 hour depending on the reaction temperature. This reaction is about 20 after adding all of the halide to the reaction mixture.
~ 30 ° C, such as 25 ° C for at least about 15 minutes, usually
The reaction rate can be increased by heating for 0.5 hour.

The corresponding compound of formula VII is formed by reacting compound (VI) with a hydride reducing agent such as diisobutylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride. The reaction is generally carried out at -78 to -10 ° C, for example about -23 ° C, in a dry inert solvent such as tetrahydrofuran, ether, toluene or benzene.

Alternatively, compound (V) is the formula R ₁ X or R ₂ X (wherein R ₁
And R ₂ are as defined above, and X is halogen such as mesylate or chloro, bromo or iodo. This reaction is advantageously carried out in the presence of a base such as sodium hydroxide, sodium t-butoxide hydride or a tertiary amine such as triethylamine.

Compounds of formula I in which —NR ₂ R ₂ is an optionally substituted pyrrolidinyl or piperidinyl include compounds of formula (I) in which R ₁ and R ₂ are hydrogen and 1,4-dibromobutane or 1,
It can be formed by reaction with 5-dibromopentane or an appropriately substituted derivative thereof. Alternatively, the compound
(I) (wherein NR ₁ R ₂ is replaced by methylsulfonyl) Formula R ₁ R ₂ NH (where R ₁ and R ₂ are at the same time as the nitrogen to which they are attached are pyrrolidinyl or piperidinyl) And these heterocycles are (C ₁ -C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety may be substituted with (C ₁ -C ₆ ) alkyl)
May be substituted with one or two of ) Amine. This method is based on The Pyrimidines, S of Brown et al.
npplementI, 226and227, Wiley-Interscience (1
970).

Compounds of formula I (provided that R ₅ is other than hydrogen) are groups readily react corresponding compound (VIII) wherein R ₅ X (X is a hydroxy group of the compound VIII is R ₅ is hydrogen, such as chlorine It is a halogen, tosyl or mesyl). When R ₅ is methyl, a methylating agent such as dimethylsulfate can be used.

The reaction is generally carried out under anhydrous conditions in a polar neutral solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Suitable reaction temperature is from about 0 ° C
It is about 100 ° C, usually 25 ° C to 30 ° C. The reaction is promoted by forming the phenolate salt of compound (VIII) by carrying out the reaction in the presence of an organic base such as triethylamine and an inorganic base such as sodium hydroxide or potassium hydroxide. In this case, the reaction is carried out in an inert atmosphere such as nitrogen to avoid oxidation of the phenolate anion.

The diketo-acyloxy compound of formula II is the corresponding diketo-
Baryler, D by acylation of halo compounds
Bull Sok Chim 1976, 44
It can be manufactured as described by 4-448. Thus, 1,3-disubstituted-2-halopropanedione-
1,3 is reacted with sodium acylate in a solvent such as dimethylsulfoxide. The halogen in this diketo compound is chlorine or bromine. The acylated product may be a suitable acylated product such as acetate or benzoate.

Diketo-halo compounds can be prepared by halogenation of the corresponding diketones, although these diketones are
Evine), Journal of American Chemical Society of R et al. (J. Am. Chem. Soc.), 67, 1510.
-1512 (1945). Thus, beta-diketones are formed by acylating a ketone with an ester with sodium amide.

The guanidine salts of formula III used in the preparation of compounds of formula I are commercially available when R ₁ and R ₂ are hydrogen or methyl.

Acid addition salts of compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base (I) with about 1 stoichiometric amount of a pharmaceutically acceptable acid. The salt is isolated using conventional concentration and recrystallization techniques. Examples of suitable acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascombic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, iodine. Hydrous acids, sulfamic acids, sulphonic acids such as methanesulphonic acid, benzenesulphonic acid and similar acids. Phosphoric acid is preferred.

Base addition salts of formula (I) in which R ₅ is hydrogen include phenol (I)
Can be prepared by reacting with about 1 chemical equivalent of an inorganic base such as an alkali metal hydroxide or alkaline earth metal hydroxide.

The compounds of formula I ′ and their pharmaceutically suitable acid and base addition salts are inhibitors of leukotriene synthesis and of various lung, gastrointestinal, inflammatory, cutaneous and circulatory disorders. In particular, these compounds are used as the sole active agent and in combination with other active agents, asthma, bronchitis, pulmonary diseases such as pulmonary hypertension and hypoxia, peptic ulcer, psoriasis, arthritis, inflammatory bowel disease. It is also useful as a therapeutic agent for cardiovascular spasm, such as acute myocardial infarction.

For the treatment of a variety of the above disorders, the compounds of formula I'can be administered to patients in need of treatment by a variety of conventional routes of administration including oral, injection, topical, and inhalation with aerosol carrier compositions.

Generally, a therapeutically effective amount of an active compound of formula I'is 0.01 to
100 mg / kg (body weight) / day, preferably 0.1-5
It is 0 mg / kg / day.

The compounds of formula I ′ can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, oral administration may be in the form of tablets containing adjuvants such as starch or lactose, or alone or in combination with supplements, elixirs or suspensions containing flavoring or coloring agents. For animals, the compounds of the invention are preferably included in animal feed or drinking water. For parenteral injection, it may be used in the form of a sterile aqueous solution containing other solute, for example, sufficient salt or glucose to make the solution isotonic.

The activity of the compounds of formula I ′ in the treatment of lung disease, asthma, allergies and inflammation is due to rat basophilic leukemia (RB
L-1) can be measured by standard tests which measure the ability of cells to inhibit cyclooxygenase and lipoxygenase enzyme activities. Jakschick et al.
Prostaglandins, 16,733-747 (197
According to this test described in 8), monolayers of RBK-1 cells were cultivated by rotary culture in a mixture of Eagle's minimum essential medium, 15% heat-inactivated fetal bovine serum and antibiotics and antimicrobials. Grow for 2 days. These cells are washed after centrifugation and incubated in buffer. Pre-incubate 0.5 m of the cell suspension at 30 ° C for 10 minutes. At this time, the test compound dimethyl sulfoxide (DMS
O) Add 1 μ of the solution to pre-incubate. Incubation was performed with ( ¹⁴ C) -arachidonic acid in 5 μm ethanol and potassium ionophore (A-21387) in 2 μm DMSO at final concentrations of 5 μM and 7.6, respectively.
Start by simultaneously adding to μM. After 5 minutes, incubate 10% of acetonitrile and acetic acid.
It is terminated by adding 0.27 m of a 0: 3 mixture. Thin layer chromatography is performed using a solvent consisting of acetonitrile, water and acetic acid.

Example The following example illustrates the invention.

Example 1. 2- (p-chlorophenylpropylamino) -4,6-
Dimethyl-5-hydroxypyrimidine _{(R 1 = R 5 = H} ;
R ₂ = p-chlorophenylpropyl; R ₃ = R ₄ = methyl) 5-acetoxy-4,6-dimethyl-2- (p-chlorophenylpropylamido) pyrimidine (0.27 g, 0.78 mmol) 3.5 m (3.5 mmol) of 1M dival (Dib
al) hexane solution at -23 ° C in tetrahydrofuran (5
m) Treated under medium nitrogen for 3 hours. This reaction mixture was added to 15
The reaction was quenched with aqueous ammonium chloride solution of m. and stirred overnight at room temperature.

The reaction mixture was passed and the liquid was extracted with a total volume of 40 m ethyl acetate. The extracts were dried, concentrated and chromatographed with a mixture of hexane and ethyl acetate 1: 1 as the eluting solvent to give 0.1 g (37%) of the crystalline title compound. mp124-126 ° C.

Example 2. 2- (p-methylphenylpropylamino) -4,6-
Dimethyl-5-hydroxypyrimidine (R ₁ = H, R ₂ =
p- methyl phenylpropyl; R ₃ = R ₄ = methyl; R ₅
= Hydrogen) 5-acetoxy-4,6-dimethyl-2- (p-methylphenylpropylamido) pyrimidine (7.7 g, 24 mmol) in hexane in a 1 molar solution of dival (94 m
, 94 mmol) in tetrahydrofuran (150 m
) As a dry solution at -35 ° C under nitrogen. 3.
After 5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 m), brought to room temperature and stirred for 1 hour. This was filtered to give a clear solution, diluted with 100 m of water and extracted with 250 m of ethyl acetate. The dried extract was concentrated and chromatographed on silica gel with a mixture of hexane and ethyl acetate 1: 1 as eluent to give 2.0 (31%) of the title compound. mp103 ~
104 ° C.

Example 3. In the same manner as in Example 1, the following compound was obtained.

2-(n-nonylamino) _{-4,6-dimethyl-5-hydroxypyrimidine; NMR (CDCl 3); 0.8-1.6} (m, 17
H), 2.25 (s, 6H), 3.1-3.4 (m, 2H); 4,6-dimethyl-5-hydroxy-2-phenylhexylaminopyridine; mp 43-45 ° C 4-isopropyl-5-hydroxy-6. -Methyl-2-
P-chlorophenylpropylaminopyrimidine; NMR (CDCl
₃ ); 7.10 (m, 4H), 4.20 (bs, 1H), 3.30 (m,
3H), 2.6 (m, 2H), 2.3 (s, 3H), 1.80
(M, 2H), 1.2 (d, 6H); and 4-isopropyl-5-hydroxy-6-methyl-2-
Nonylaminopyrimidine; NMR (CDCl ₃ ): 6.30 (bs, 1
H), 4.75 (bs, 1H), 3.55-3.10 (m, 3H), 2.
30 (s, 3H), 1.60-0.90 (m, 23H).

Example 4. A. A mixture of 3-acetoxy-5-methyl-2,4-hexanedione (5 g, 27 mmol) and guanidine acetate (6.4 g, 54 mmol) in 100 m of dimethylformamide was heated at 100 ° C for 3 hours. . After cooling, the thick reaction was passed through a pad of silica gel using an equal volume mixture of hexane and ethyl acetate as eluent. The solution was concentrated and the residue was treated with excess acetic anhydride in the presence of triethylamine. The reaction mixture was concentrated and the residue was crystallized from boiling hexane to give 1.7 g (31%) of 5-acetoxy-2-amino-4-isopropyl-6-.
Methylpyrimidine was obtained. mp 141-142 ° C B.5-acetoxy-2-amino-4-isopropyl-6
-Methylpyrimidine (0.5 g, 2.4 mmol) in pyridine 6-phenylhexanoic acid chloride (3.6 mmol)
At 0 ° C. for 0.5 hours. The reaction mixture was warmed to 25 ° C and maintained at that temperature for 0.5 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel with a 3: 1 mixture of hexane and ethyl acetate as eluent to give 0.66 g (72%) of 5-acetoxy-4-isopropyl-6-methyl-2. -Phenylhexylamide pyrimidine was obtained.

_{NMR (CDCl 3): 8.28 (} bs, 1H), 7.20 (s, 5H), 3.
20-2.50 (m, 5H), 2.35 (s, 3H), 2.25 (s,
3H), 1.90-1.40 (m, 6H), 1.08 (d, 6H).

The compound prepared in CB was reacted according to the method of Example 3 to produce 4-isopropyl-5-hydroxy-6-methyl-2-phenylhexylaminopyrimidine having a melting point of 60-6.1 ° C.

Example 5. 2-Dimethylamino-4-isopropyl-6-methyl-
5-hydroxypyrimidine (R ₁ = R ₂ = methyl; R ₃ =
Isopropyl, R ₄ = methyl) A. 3-acetoxy-5-methyl-2,4-hexadione (3 g, 16 mmol), 1,1-dimethylguanidine sulphate (4.4 g, 16 mmol) and sodium acetate (2.6 g). , 32 mmol) in dimethylformamide and heated in a nitrogen atmosphere at 100 ° C. for 4 hours. The reaction mixture was cooled and concentrated. Chromatography on silica gel with a 9: 1 mixture of hexane: ethyl acetate as eluent gives 0.4 g of a brown oil, 5.
-Acetoxy-2-dimethylamino-4-isopropyl-6-methylpyrimidine was obtained.

_{NMR (CDCl 3): 3.2 (} s, 6H), 3.0-2.5 (s, 3
H), 2.1 (s, 3H), 1.1 (d, 6H).

The compound prepared in B.A (0.3 g, 1.3 mmol) was dissolved in dry tetrahydrofuran, cooled in a nitrogen atmosphere at -35 ° C and a 1M solution of dival in hexane (2.6 m, 2.6 m).
Mmol). After 1 hour, the reaction mixture was brought to 0 ° C. over 1 hour and quenched with 10 m of aqueous ammonium chloride solution. The mixture is filtered, extracted with 25m ethyl acetate, dried over magnesium sulphate and concentrated.
0.24 g of the title compound was obtained. mp 82-83 ° C.

Example 6. 2-Dimethylamino-4 prepared by the method of Example 5A
2-Dimethylamino-4-methyl-6-phenyl-5-hydroxypyrimidine having a melting point of 125.5-127.5 ° C. was obtained from -methyl-6-phenyl-5-acetoxypyrimidine by the method of Example 5B. _{NMR (CDCl 3): 8.3-73 (} m, 5
H), 3.3 (s, 6H), 2.3 (s, 3H), 2.1 (s,
3H).

Example 7. The following intermediate was prepared in a similar manner to the method of Example 4B: 5-acetoxy-2-p-chlorophenylpropylamino-4-isopropyl-6-methylpyrimidine; NMR (CD
_{Cl 3): 7.20 (s,} 4H), 3.3-2.7 (m, 5H), 2.35
(S, 3H), 2.30 (s, 3H), 1.21 (d, 6H);
And 5-acetoxy-2-n-nonyl-4-isopropyl-
_{6-methyl-pyrimidine; NMR (CDCl 3); 3.5-2.8} (m, 3
H), 2.35 (s, 2H), 2.30 (s, 3H), 1.5-0.8
(M, 21H).

Example 8. 2- (p-Chlorophenylpropylamino) -4-phenyl-5-hydroxypyrimidine 2-amino-5-benzoyloxazole (3.0 g, 1
6 mmol) to p-chlorophenylpropylamine (2.
(7 g, 16 mmol) and 15 m of water and t-butanol 2: 1 in a mixture and heated to reflux under nitrogen for 16 hours. The solvent was removed in vacuo and the residue was treated with hot acetonitrile and passed. After concentrating in vacuo, the liquor on silica gel using a mixture of hexane and ethyl acetate 1: 1 as eluent gave 0.24 mg (4.4%) of the title compound as an oil.

_{NMR (CDCl 3): 1.8-2.0 (} m, 2H), 2.4-2.7 (m, 2
H), 3.1-3.4 (m, 2H), 5.0 (bs, 1H), 7.0-
7.5 (m, 7H), 7.8 (s, 1H), 7.9-8.0 (m, 2
H).

Example 9. The following compounds were prepared similarly to the method of Example 8: Example 10. 4- (3,4-Dichlorophenyl) -2-dimethylamino-5-hydroxypyrimidine 2-amino-5- (3 ', 4'-dichlorobenzoyl)
Oxazole (2 g, 7.8 mmol) was stirred with aqueous dimethylamine (100 m) in t-butyl alcohol and stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel with a mixture of hexane and ethyl acetate 3: 1 as eluent to give 1.5 g of the title compound as a crystalline solid. mp188-189
° C.

Similarly to Example 11. Example 8, following compounds were prepared: 2-(n-nonylamino) _{-4-phenyl-5-hydroxypyrimidine; NMR (CDCl 3): 0.9-1.7} (m, 17H), 3.1-3.6 (M,
2H), 7.35-7.55 (m, 3H), 7.8 (s, 1H),
8.0-8.25 (m, 2H); 2-dimethylamino-4- (4-fluorphenyl)-
5-hydroxypyrimidine, mp159-160 ℃; 2- phenylene _{ethylhexyl-amino-4-phenyl-5-hydroxypyrimidine; NMR (CDCl 3): 1.4} (m, 8H), 2.5 (m, 2H), 3.38
(Bs, 1H), 4.8 (bs, 1H), 6.95-7.4 (m, 8
H), 7.8 (s, 1H ), 7.9-8.1 (m, 2H); and 2-(n-hexylamino) _{-4-phenyl-5-hydroxypyrimidine; NMR (CDCl 3); 8.2-8} (m, 2H), 7.8 (s, 1H),
7.4-7.2 (m, 3H), 5.0 (bs, 1H), 3.3 (m, 2)
H), 1.5-0.9 (m, 11H ) Example 12. = 4,6-dimethyl-5-methoxy-2-phenylpropyl pentyl aminopyrimidine _{(R 1 H; R 2 =} 2- Fuenpenchiru; R ₃ = R ₄ = R ₅ = CH ₃ ) 4,6-dimethyl-5-hydroxy-2-phenpentylaminopyrimidine prepared by the method of Example 1 (0.5 g, 1.8
Sodium hydride (0.07 g, 1.8 mmol, 60%) was dissolved in dry THF (20 m) under nitrogen.
Suspension in oil). The reaction mixture was stirred at 0 ° C. for 2 hours. Dimethyl sulphate (0.11 m, 1.8 mmol) was injected and the reaction was stirred for another hour. Saturated NH
_After quenching with ₄ Cl (aq, 20 m), the reaction mixture was extracted with ethyl acetate (75 m). The extracts were washed with brine 50m of water and 50m, and concentrated and dried over MgSO _4. Chromatography on silica gel using a 1: 1 mixture of ethyl acetate and hexane as eluent gave 0.15 g of the title compound as a yellow oil. mp
31-33 ° C.

_{NMR (CDCl 3): 7.2 (} s, 5H), 3.6 (s, 3H), 3.4
(M, 2H), 2.6 (m, 2H), 2.3 (s, 6H), 1.
6-1.4 (m, 6H) Example 13. By the method of Example 12, 4,6-dimethyl-5-methoxy-2-phenylhexylaminopyrimidine was prepared.

_{NMR (CDCl 3): 7.14 (} bs, 5H), 4.9 (bs, 1H), 3.6
3 (s, 3H), 3.4 (m, 2H), 2.6 (m, 2H),
2.3 (s, 6H), 1.3-1.4 (m, 8H) Example 14. 5-methoxy-4-methyl-2-phenylene hexyl aminopyrimidine _{(R 1 = H; R 2} = 2- Fueniruhekishiru; R ₃ = H _{; R 4 = R 5 = CH} 3) sodium hydride (60% in oil suspension, 58 mg, 2 Kaiarai ivy 1.45 mmol) in dry nitrogen filled flask pentane. The residue was slurried in 4 m of dry THF, 32
0 mg (1.1 mmol) 5-methoxy-4-methyl-2
-Phenylhexylaminopyrimidine was added portionwise at 0 ° C. After stirring for 30 minutes, add dimethyl sulphate,
The reaction mixture was cooled to room temperature over 1 hour, diluted with 10 m saturated ammonium chloride and 4 times with 25 m portions of ethyl acetate. The extracts were chilled, dried over magnesium sulphate and concentrated to 374 mg oil. Chromatography on silica gel with a mixture of ethyl acetate and hexane (1: 1) gave 130 mg of an oil,
This was left to stand and crystallized. 39 crystallized title compound
It had a melting point of -40 ° C.

Example 15. In analogy to the method of Example 14, 4- (3,4-dichlorophenyl) -2-dimethylamino-5-methoxypyrimidine, mp 72-73 ° C; 4- (3,4-dichlorophenyl) -2-dimethyl. Amino-5-ethoxypyrimidine,
mp 69-70 ° C; and 2- (p-chlorophenpropylamino) -4,6-dimethyl-5-methoxypyrimidine, mp 84-85 ° C.

Example 16. 2-Dimethylamino-4-methyl-5-benzyloxy-pyrimidine _{(R 1 = R 2 = R} 4 = CH 3; R 3 =
H; R ₅ = benzyl) Potassium hydroxide (85%, 2.64 g, 40 mmol) was powdered and added at room temperature in DMSO of 20 m. 2-Dimethylamino-4-methyl-5-hydroxypyrimidine (1.53 g, 10 mmol) was added and the reaction mixture was stirred for 5 minutes at room temperature. Benzyl iodide (1.2 m, 10 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature, then 50 m.
Of water. The reaction mixture was extracted 4 times with 50 m each of hexane. Hexane Extract
_It was dried over ₂ SO ₄ and evaporated. The obtained solid was recrystallized from hexane to obtain 1.8 g (yield 75%) of the title compound as pale yellow crystals. mp 73-74 ° C.

Example 17. 2-Dimethylamino-4-as described in Example 16
Methyl-5-methoxypyrimidine was prepared. mp18
9-190 ° C (hydrochloride).

Example 18. 2- (2-dimethylamino-5-methoxy-pyrimidin-4-yl) - ethyl acetate _{(R 1 = R 2 = R} 5 = C
_{H 3; R 3 = H;} R 4 = CH 2 CO 2 C 2 H 5) septum 1 of 11.6 m (18.6 mmol) under a nitrogen atmosphere in a three-neck flask low temperature thermometer and an addition funnel with 150 meters.
6Mn-butyllithium was added. This flask at 5 ° C
After cooling to 2.6 m (18.6 mmol) of diisopropylamine in 20 m of dry THF was added dropwise over 5 minutes. After the addition was complete, the mixture was stirred at 5 ° C for 15 minutes,
Cooled to -70 ° C. To this reaction mixture was added a solution of 1.56 g (9.3 mmol) 2-dimethylamino-4-methyl-5-methoxypyrimidine in 20 m dry THF over 10 minutes. The reaction mixture was then stirred at -70 ° C for 1.5 hours and 20 ml of ethyl chloroformate in dry THF.
0 g (18.6 mmol) of solution was added over 5 minutes. The reaction mixture was stirred at -70 ° C for 30 minutes and then cooled to -15 ° C.
The temperature was raised over the course of minutes. The reaction mixture was brought to pH with 1N HCl.
It was adjusted to 8.5 and extracted 3 times with 25 m of each chloroform. The extracts were chilled, dried over Na ₂ SO ₄ and evaporated to leave an oil. Chromatography on 100 g of silica gel with a mixture of hexane and ethyl acetate 9: 1 gave 47% (1.05 g) of the title compound as a colorless liquid.

NMR (CDCl ₃ ): 8.0 (s, 1H), 4.19 (q, J = 7H
z, 2H), 3.75 (s, 3H), 3.65 (s, 2H), 3.
05 (s, 6H), 1.1 (t, J = 7Hz, 3H) Example 19. 2-Phenylhexylamino-4-methyl-5
-Hydroxypyrimidine sodium salt Sodium hydride (50% suspension in oil, 337 mg) was washed with hexane to remove oil, dried under vacuum and stirred in tetrahydrofuran. The slurry formed was cooled in ice and 2- (n-hexylphenyl) -4-methyl-5-hydroxypyrimidine in tetrahydrofuran (2g).
Processed in. The cold mixture was stirred cold at 0 ° C. for 30 minutes and concentrated to give a greenish foam. Ethyl alcohol was added and the mixture was concentrated. Toluene was added and the mixture was concentrated in vacuo to give a solid. Yield 2.01g, mp128-131
° C.

Example 20. 2-Phenylpentylamino-4,5-dimethyl-5-methoxypyrimidine phosphate.

1.09 g of 2-phenylpentylamino-4,6-dimethyl-5-methoxypyrimidine was dissolved in 15 m of isopropyl alcohol and cooled to 0 ° C. Phosphoric acid (85
%, 9 g) and the mixture was stirred at 0 ° C. for 30 minutes. A white solid precipitated, the isopropanol was removed, washed with pentane and the solid was collected by drying in vacuo at 45 ° C. Melting point 107-108 [deg.] C.

Example 21. The following compound was prepared by a method similar to that of Example 20:

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/505 ABG 9360-4C ABS 9360-4C ACD 9360-4C ACL 9360-4C ADA 9360-4C

Claims (8)

[Claims] 1. A formula [Wherein R ₁ is hydrogen or (C ₁ -C ₁₅ ) alkyl; R ₂
Is hydrogen, (C ₁ -C ₁₅ ) alkyl, cyclopentyl, cyclohexyl, (C ₃ -C ₁₅ ) alkenyl, phenyl,
Or (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety is fluoro, chloro, (C ₁ -C ₃ ) alkyl,
It may be substituted with one or two of (C ₁ -C ₃ ) alkoxy or CF ₃ . ); Or R
₁ and R ₂ together with the nitrogen atom to which they are attached are pyrrolidinyl optionally substituted by one (C ₁ -C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ) phenylalkyl. Or forms piperidyl; R ₃ is (C ₁
--C ₆ ) alkyl, phenyl, (C ₇ -C ₂₀ ) phenylalkyl (wherein the phenyl moiety is fluoro, chloro, (C
₁ -C ₃₎ alkyl, (C ₁ -C ₃₎ alkoxy or CF
Optionally substituted with one or two of the _three), or may be substituted with one (C ₁ -C ₃₎ alkyl, furyl or thienyl; R ₄ is hydrogen, (C ₁
--C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ) phenylalkyl (wherein these phenyl are fluoro, chloro, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ R ₅ is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl or (C ₇ -C ₂₀ ) phenylalkyl (wherein these phenyls are fluoro). , Chlor, (C ₁ −
C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or CF ₃ which may be substituted with one or two of R ₃ ) and R ₅ is hydrogen, and (1) R ₃ and When R ₄ is each methyl, R ₁ and R ₂ are not each hydrogen, and (2) R ₃
And R ₄ are each phenyl, then R ₁ and R ₂ are not each methyl, (3) When R ₃ is (C ₁ -C ₆ ) alkyl, R ₄ is not hydrogen, and (4) R _{When 4} and R ₅ are hydrogen, R ₃ is not (C ₁ -C ₆ ) alkyl. ] Or an acid addition salt thereof or a base addition salt thereof when R ₅ is hydrogen. 2. R ₂ is hydrogen, (C ₁ -C ₁₅ ) alkyl or (C ₇ -C ₂₀ ) phenylalkyl, wherein the phenyl moiety is one of chloro or (C ₁ -C ₃ ) alkyl. Or optionally substituted with two); R ₃ is (C _1-
C ₆ ) alkyl or phenyl (fluor, chloro,
Optionally substituted with one or two of methyl, ethyl, methoxy, ethoxy or CF ₃ ); R
The compound of claim ₁ wherein ₄ is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl or phenyl substituted with one or two methyl or ethyl. 3. R ₂ is (C ₉ -C ₁₂ ) phenylalkyl,
(C ₈ -C ₉ ) alkyl, (C ₉ -C ₁₂ ) p-chlorophenylalkyl or (C ₁₀ -C ₁₃ ) p-methylphenylalkyl, as claimed in claim 1 or 2. Compound. 4. A compound according to claim 1 or 2, wherein R ₁ and R ₂ are each (C ₁ -C ₆ ) alkyl. 5. The compound according to any one of claims 1 to _{4, wherein} R ₃ and R ₄ are each methyl. 6. A compound according to claim 1 selected from the following compounds: 2- (p-chlorophenylpropylamino) -4,6-
Dimethyl-5-hydroxypyrimidine, 2- (p-methylphenylpropylamino) -4,6-dimethyl-5-
Hydroxypyrimidine, 2- (n-nonylamino)-
4,6-Dimethyl-5-hydroxypyrimidine, 2-phenylhexylamino-4,6-dimethyl-5-hydroxypyrimidine and 2-dimethylamino-4-p-fluorphenyl-5-hydroxypyrimidine. 7. The compound according to any one of claims _{1 to 6, wherein} R ₅ is (C ₁ -C ₆ ) alkyl. 8. The compound according to any one of claims 1 to 7, wherein the acid addition salt is a phosphoric acid addition salt.